Renal-friendly Li⁺-doped carbonized polymer dots activate Schwann cell autophagy for promoting peripheral nerve...

Activation of autophagy in Schwann cells (SCs) has emerged as a powerful trigger for peripheral nerve injury (PNI) repair. Lithium ion (Li⁺) is a classical autophagy activator that plays an important role in promoting axonal extension and remyelination. However, the therapeutic window of existing lithium drugs is extremely narrow, and the adverse side effects, especially nephrotoxicity, severely limit their therapeutic value. Herein, Li⁺-doped carbonized polymer dots (Li-CPDs) was synthesized for the first time to change the pharmacokinetics of Li⁺ from occupying epithelial sodium channels to lipid raft-mediated endocytosis. The in-vivo results confirmed that Li-CPDs could accelerate the removal of myelin debris and promote nerve regeneration via activating autophagy of SCs. Moreover, Li-CPDs exhibited almost no renal toxicity compared to that of raw lithium drugs. Thus, Li-CPDs could serve as a promising Li⁺-based nanomedicine for PNI regeneration with improved biosafety. STATEMENT OF SIGNIFICANCE: Regardless of the fact that lithium drugs have been used in treatment of mental illness such as manic depression, the systemic side effects and renal metabolic toxicity still seriously restrict their clinical application. Since Li⁺ and Na⁺ compete for ion channels of cell membrane, the cell entry efficiency is extremely low and easily affected by body fluctuations, which seems to be an unsolvable problem. Herein, we rationally exploited the endocytotic features of CPDs to develop Li-CPDs. The Li-CPDs improved the entry pathway, greatly reduced nephrotoxicity, and inherited the biological function of Li⁺ to activate autophagy for promoting peripheral nerve regeneration. Due to the BBB-crossing property of Li-CPDs, it also showed application prospects in future research on central nervous system diseases.